We seek to develop an aerosol delivery approach to more effectively treat and improve the control over transmission and outbreak of respiratory infectious diseases, specifically tuberculosis (TB) and multi-drug resistant TB (MDR-TB). Our hypothesis is that direct, topical delivery of antibiotics to infected lungs results in relatively high local drug concentrations, which can more quickly eradicate active bacterial populations, thus sterilizing the lungs and reducing the duration of infectivity and the duration of chemotherapy necessary to achieve a durable cure in pulmonary tuberculosis relative to parenteral or oral dosing. We propose to develop and test anti-TB agents and combinations that can be administered directly to patient lungs from an inexpensive, easy-to-use inhaler suitable and appropriate for use even in resource-limited settings. The agents will be formulated into large porous particles (LPPs) whose unique physical characteristics enable highly efficient delivery of relatively large drug masses. This approach has the added advantages of being non-invasive and/ or reducing gastrointestinal and systemic side effects. Specific research aims are to develop stable, LPP formulations of key anti-TB agents, establish their efficacy in animal models of TB, complete 28-day toxicology testing, and to determine reliability in the field of an existing inhaler by challenging it harsh conditions. This work will result in the identification of lead candidate antibiotic aerosols suitable for further clinical development for the improved treatment of TB and MDR-TB. It represents a new paradigm for treating and limiting the spread (especially nosocomial transmission) of respiratory infectious diseases such as TB, severe acute respiratory syndrome (SARS), influenza, and small pox.